This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The continued evolution of the virtual cell requires the ability to gracefully extend the supported modeling domains as well as provide additional tools for analysis and interoperability. Drawing on our experience with the development of the existing Virtual Cell, we are now poised to define a generalized architecture for modeling and simulation for spatial and non-spatial modeling and simulation of cell physiology. The existing layered modeling approach of the Virtual Cell will be considerably generalized into a specification of abstract layers with clear semantics, clear interfaces and flexible representation and implementations. We will define a number of abstract services on these abstract data types and provide reference implementations of both data (models, data, mathematics) and services (solvers, analyzers, translators, mappings between layers). Through the use of an extensible set of translators and adapters, existing data formats (e.g. SBML, CellML, VCML) and tools (exiting and third party solvers, model analysis, data analysis and fitting) can be integrated within the modeling process. A high level modeling ontology will be created to formalize the semantic definitions, referencing or importing appropriate domain specific ontologies such as SBO.